Trimethylamine N-oxide (TMAO) is an organic compound with the formula (CH3)3NO. It is in the class of amine oxides. Although the anhydrous compound is known, trimethylamine N-oxide is usually encountered as the dihydrate. It is a product of the oxidation of trimethylamine, a common metabolite in animals. Both the anhydrous and hydrated materials are white, water-soluble solids.

Trimethylamine N-oxide is an osmolyte found in saltwater fish, sharks, rays, molluscs, and crustaceans. It is considered as a protein stabilizer that may serve to counteract urea, the major osmolyte of sharks, skates and rays. It is also higher in deep-sea fishes and crustaceans, where it may counteract the protein-destabilizing effects of pressure.[1] TMAO decomposes to trimethylamine (TMA), which is the main odorant that is characteristic of degrading seafood.

Trimethylaminuria is a rare defect in the production of the enzyme flavin containing monooxygenase 3 (FMO3).[3][4] Those suffering from trimethylaminuria are unable to convert choline-derived trimethylamine into trimethylamine oxide. Trimethylamine then accumulates and is released in the person's sweat, urine, and breath, giving off a strong fishy odor.

The order Clostridiales, the genus Ruminococcus, and the taxon Lachnospiraceae are positively associated with TMA and TMAO levels.[5] In contrast, proportions of S24-7, an abundant family from Bacteroidetes, are inversely associated with TMA and TMAO levels.[5]

Studies published in 2013 indicate that high levels of TMAO in the blood are associated with an increased risk of major adverse cardiovascular events.[6] The concentration of TMAO in the blood increases after consuming foods containing carnitine[7] or lecithin[6] if the bacteria that convert those substances to TMAO are present in the gut.[8] High concentrations of carnitine are found in red meat, some energy drinks, and some dietary supplements; lecithin is found in soy, eggs,[8] as an ingredient in processed food and is sold as a dietary supplement. Some types of normal gut bacteria (e.g. species of Acinetobacter) in the human microbiome convert dietary carnitine to TMAO. TMAO alters cholesterol metabolism in the intestines, in the liver, and in artery walls. In the presence of TMAO, there is increased deposition of cholesterol in, and decreased removal of cholesterol from peripheral cells such as those in artery walls.[9]

The link between cardiovascular diseases and TMAO is disputed by other researchers[10] who are employees of Lonza, a company that sells carnitine.[11] Clouatre et al. argue that choline sources and dietary L-carnitine do not contribute to a significant elevation of blood TMAO, and the main TMAO source in the diet is fish.[12]

Another source of TMAO is dietary phosphatidylcholine, again by way of bacterial action in the gut. Phosphatidyl choline is present at high concentration in egg yolks and some meats.

It has been suggested that TMAO may be involved in the regulation of arterial blood pressure and etiology of hypertension[13] and thrombosis (blood clots) in atherosclerotic disease.[14] A 2017 meta-analysis found higher circulating TMAO was associated with 23% higher risk of cardiovascular events and a 55% higher risk of mortality.[15]

Vegan and vegetarian diets appear to select against gut flora that metabolize carnitine (in favor of other gut flora more coordinated with their food supply). This apparent difference in their microbiome is associated with substantially reduced gut bacteria capable of converting carnitine to trimethylamine, which is later metabolized in the liver to TMAO.[7]

3,3-Dimethyl-1-butanol (DMB), a structural analog of choline, inhibits microbial TMA formation in mice and in human feces, thereby reducing plasma TMAO levels after choline or carnitine supplementation.[5] It is found in some balsamic vinegars, red wines, and some cold-pressed extra virgin olive oils and grape seed oils.[5]

Resveratrol has been shown to reduce TMAO in mice by remodeling gut microbiota.[16]

The effects of TMAO on the backbone and charged residues of peptides are found to stabilize compact conformations,[17] whereas effects of TMAO on nonpolar residues lead to peptide swelling. This suggests competing mechanisms of TMAO on proteins, which accounts for hydrophobic swelling, backbone collapse, and stabilization of charge-charge interactions. These mechanisms are observed in Trp cage.[18]